The process of initiating and perpetuating asthmatic inflammation occurs as a result of a complex array of factors, predominantly Th2 cytokines from activated T cells, mast cells and eosinophils. These cytokines have been fairly well described in asthma and are considered to be pro-inflammatory. Factors that function to modulate the asthmatic response, either during the acute inflammatory phase or associated with resolution of inflammation, have not been as well characterized. In this project application, we present data indicating that IL-16 is produced by airway epithelial cells early in the human asthmatic response following cytokine stimulation by the Th2 cytokines IL-9 and IL-13, as well as tumor necrosis factor (TNF) and Fas ligand (FasL). In conjunction with Project 4, IL-16 promoter sequence analysis has identified a SNP, present in 30 percent of individuals tested. Expression of the SNP sequence prevents IL-9-induced IL-16 production. to determine in vivo relevance of this finding we propose to assess alterations in cytokine responsiveness, for IL-16 production, using a panel of murine epithelial cell lines. A murine strain has been identified which expresses the SNP sequence. A variety of mouse strains will be sequenced and presence of the SNP correlated with severity of airway reactivity and inflammation. This will be performed in parallel with Project 4 where presence of the SNP will be correlated with severity of disease in asthmatic and non-asthmatic individuals. With the use of exogenous administration of IL-16 protein or using an IL-16-/- mouse in an OVA model of airway inflammation and hyper-responsiveness to methylcholine, we demonstrate that IL-16 acts to modulate the asthmatic response. The use of IL-16 transgenic (Tg)+ and IL-16-/- crossed with the IL-9 Tg+ will better characterize this effect, and bone marrow transplant studies using the IL-16 Tg+ and IL-16-/- will identify the major cell source in the lung. Completion of these studies will confirm the hypothesis that IL-16 is an immunomodulatory cytokine in asthma and will also identify a novel therapeutic approach for treatment of asthma.